Classical notions of receptor pharmacology imply that when a ligand interacts with a receptor, only a unitary outcome is possible. According to these models of receptor pharmacology, a full or partial agonist can activate only a single signal transduction pathway while an antagonist can only block the actions of an agonist. The key theoretical construct underlying this model was the concept of intrinsic efficacy (Furchgott, Advances in Drug Research (Harper N and Simmonds A eds) Academic Press, New York., pp 21-55 (1966)). According to this conceptualization, a full agonist has maximum intrinsic efficacy and maximally stimulates all cellular responses induced by ligand binding. A partial agonist possesses a lower degree of intrinsic efficacy and partially activates all cellular responses induced by an agonist. Antagonists, according to this schema, are neutral entities which possess no intrinsic activity but are able to block the receptor and preclude activation by full or partial agonists (Furchgott, Advances in Drug Research (Harper N and Simmonds A eds) Academic Press, New York., pp 21-55 (1966)). An extension of this model has been that a single G-protein coupled receptor (GPCR) interacts with a single G protein subtype (e.g., Gi, Gs, Gq, Go and so on) and that full and partial agonists activate only a single transduction pathway.
For many decades, however, it has been clear that these simplistic notions of GPCR (also known as 7-transmembrane receptor or 7-TM) function cannot account for the myriad of actions induced by agonist or antagonist binding. This was first convincingly demonstrated for the serotonin (5-hydroxytryptamine; 5-HT) and dopamine (DA) families of receptors where it has been demonstrated that: (1) agonists differentially activate distinct signal transduction pathways (Beaulieu et al., J. Neurosci. 27:881 (2007); Berg et al., Mol. Pharmacol. 54:94 (1998); Ghosh et al., J. Med. Chem. 39:549 (1996); Kilts et al., J. Pharmacol. Exp. Ther. 301:1179 (2002); Mottola et al., J. Pharmacol. Exp. Ther. 301:1166 (2002); Parrish et al., J. Neurochem. 95:1575 (2005); Roth and Chuang, Life Sci. 41:1051 (1987); Urban et al., J. Pharmacol. Exp. Ther. 320:1 (2007)); (2) antagonists can possess negative intrinsic activity (e.g., function as inverse agonists) or be silent and thereby block the actions of an inverse agonist (e.g., neutral antagonists) (Barker et al., J. Biol. Chem. 269:11687 (1994); Burstein et al., J. Pharmacol. Exp. Ther. 315:1278 (2005); Chidiac et al., Mol. Pharmacol. 45:490 (1994); Gilliland and Alper, Naunyn Schmiedebergs Arch. Pharmacol. 361:498 (2000); Rauser et al., J. Pharmacol. Exp. Ther. 299:83 (2001)); (3) antagonists can also induce receptor down regulation (Peroutka and Snyder, Science 210:88 (1980)) and receptor internalization in vitro (Berry et al., Mol. Pharmacol. 50:306 (1996)) and in vivo (Gray and Roth, Brain Res. Bull. 56:441 (2001); Willins et al., Ann. NY Acad. Sci. 861:121 (1998); Willins et al., Neuroscience 91:599 (1999))—properties typically associated with agonists.
The processes by which agonists and antagonists differentially modulate signaling pathways and receptor trafficking have been variously dubbed ‘functional selectivity’, ‘biased agonism’ or ‘agonist-directed trafficking’. Currently, the preferred term for the process by which ligands can differentially activate signaling pathways mediated via a single GPCR is functional selectivity (Urban et al., J. Pharmacol. Exp. Ther. 320:1 (2007)). Functional selectivity has been demonstrated for more than a dozen GPCRs (reviewed in (Urban et al., Neuropsychopharmacology 32:67 (2007)) and is, likely, a ubiquitous phenomenon. In particular, functional selectivity has been widely observed among DA receptor subtypes.
It is desirable to identify novel, functionally selective ligands of dopamine D2 receptors to elucidate the key signal transduction pathways essential for antipsychotic efficacy and the undesired ones associated with side-effects. Such compounds would also be useful agents for treating central nervous system (CNS) disorders including schizophrenia and depression.